Process for making mycophenolate mofetil by transesterification

ABSTRACT

A process for making mycophenolate mofetil comprising: conducting a catalytic transesterification by reacting a low-carbon alkyl ester of mycophenolic acid with 2-morpholinoethanol [also named as 4-(2-hydroxyethyl) morpholine] to obtain a crude product of mycophenolate mofetil, which is then isolated and purified.

BACKGROUND OF THE INVENTION

[0001] U.S. Pat. No. 5,247,083 to Martin Knox et al. disclosed a processfor making mycophenolate mofetil by refluxing mycophenolic acid with2-morpholinoethanol in an inert organic solvent even without the use ofcatalyst. However, the reaction requires a long time period. Forexample, when the reaction completion was 94.9% by refluxing thereaction mixture at 125˜129° C., it already consumed 63 hours. The longreaction time may increase the production cost and may also waste energywhen heating the reaction mixture for such a long time period.

[0002] U.S. Pat. No. 4,753,935 to Peter H. Nelson et al. disclosed aprocess for making mycophenolate mofetil by first reacting mycophenolicacid (MPA) with thionyl chloride to be an acyl chloride of the MPA,which is then reacted with 2-morpholinoethanol to obtain themycophenolate mofetil. However, this process may be accompanied withunexpected side reactions, thereby causing serious impurities of thereaction and decreasing the yield of the final product.

[0003] The present inventor has found the drawbacks of the conventionalprocess and invented the present process for making mycophenolatemofetil by shortening the reaction time in order to reduce theproduction cost and improve the product purity.

SUMMARY OF THE INVENTION

[0004] The object of the present invention is to provide a process formaking mycophenolate mofetil comprising: conducting a catalytictransesterification by reacting a low-carbon alkyl ester of mycophenolicacid with 2-morpholinoethanol [also named as 4-(2-hydroxyethyl)morpholine] to obtain a crude product of mycophenolate mofetil, which isthen isolated and purified.

DETAILED DESCRIPTION

[0005] For a direct esterification of mycophenolic acid with2-morpholinoethanol [or named as 4-(2-hydroxyethyl) morpholine], thereaction is difficult and may take a longer reaction time period.

[0006] One way may be considered is to first activate the mycophenolicacid (MPA) to be an acyl chloride or acid anhydride of the MPA, and thenreacted with 2-morpholinoethanol to produce mycophenolate mofetil (suchas taught by U.S. Pat. No. 4,753,935). However, the activity may be toostrong, thereby accompanying with unexpected side reactions andseriously causing impurities of the product.

[0007] Accordingly, the mycophenolic acid may be first esterified, andthen reacted with the 2-morpholinoethanol to obtain the mycophenolatemofetil in accordance with the present invention.

[0008] This invention discloses a process by preliminarily conducting anesterification of the mycophenolic acid with an alkyl alcohol of lowcarbon alkyl group (C₁˜C₄) to form a low-carbon alkyl ester, which isthen reacted with the 2-morpholinoethanol to obtain the mycophenolatemofetil.

[0009] The mycophenolate mofetil (1) of the present invention isobtained by the transesterification of the alkyl mycophenolate (2) with2-morpholinoethanol (3) in the presence of a catalyst as shown in thefollowing reaction formula:

[0010] wherein R is an alkyl group selected from the group consisting ofmethyl, ethyl, propyl and butyl.

[0011] After the completion of transesterification, the reaction liquidis added therein with aqueous solution of sodium bicarbonate and ethylacetate to form a water layer and an organic layer. An aqueous solutionof acid such as hydrochloric acid is added into the organic layer toobtain a hydrochloric acid salt of mycophenolate mofetil which issoluble in water; while the unreacted alkyl mycophenolate (2) is notformed as a hydrochloric acid salt (HCl salt) and is soluble in organicsolvent to thereby be easily separated from the HCl salt ofmycophenolate mofetil by using an organic solvent to extract and removethe unreacted methyl mycophenolate. Then, an aqueous solution of basesuch as sodium hydroxide is provided to neutralize the hydrochloric acidto recover the mycophenolate mofetil which is then extracted by anorganic solvent.

[0012] The catalyst as used in this esterification may be selected fromthe group consisting of: alkaline metal salt, alkaline earth metal salt,tin oxides and stannous oxides, and may preferably be dibutyl tin oxide,having a catalyst content of 1˜200 (weight) %, preferably 5˜70 (weight)%, based on the weight of alkyl mycophenolate.

[0013] The quantity of 2-morpholinoethanol as used in thetransesterificaton may range in 1˜20 equivalents, preferably being1.01˜2 equivalents. The esterification reaction temperature is 30˜180°C., and preferably being 80˜160° C. The organic solvent as used in thereaction may be selected from the group consisting of: benzene, toluene,xylene and the mixture thereof. The reaction may also preclude the useof any organic solvent. The organic solvent used for extraction in thisinvention may be selected from: benzene, toluene, xylene, ethyl acetate,dichloro-methane, and the mixture thereof; or any other water-insolubleorganic solvent.

[0014] The present inventions may be further described in detail withreference to the following example, which is given for description, notto limit the scope of the present invention.

[0015] The alkyl mycophenolate may be obtained by reacting the MPA withan alkyl alcohol in the presence of a catalyst overnight (less than 24hours) to be the alkyl mycophenolate, such as methyl mycophenolate asshown in Example 1.

EXAMPLE 1

[0016] In a reactor, 20.0 grams (59.8 milli moles) methyl mycophenolate,8.2 g (62.6 milli moles) 2-morpholinoethanol, 40 ml toluene and 7.4 g(29.8 milli moles) dibutyl tin oxide were added. The reaction mixture(liquid) was heated until an internal temperature 120° C. was reachedand the temperature (120° C.) was maintained for performing thetransesterification reaction for 24 hours.

[0017] As checked by HPLC at this moment, there was 1.3% methylmycophenolate still unreacted. The reaction mixture was cooled to roomtemperature, added with 100 ml aqueous solution of saturated sodiumbicarbonate and 100 ml ethyl acetate, and further agitated for 5minutes. The insoluble matters were filtered off by celite. A separatingfunnel was provided for separating the aqueous layer and the organiclayer. The aqueous layer was extracted with an organic solvent, i.e.,100 ml ethyl acetate.

[0018] The organic layer combined with the organic solvent, which maycontain the mycophenolate mofetil and the unreacted reactants, was addedtherein with 200 ml water, and further acidified to be an acidicsolution by adding 6N hydrochloric acid to obtain a pH value of 1.5. Themycophenolate mofetil was formed as a hydrochloric acid salt totherefore be soluble in the water of the acidic solution while themethyl mycophenolate was not formed as a hydrochloric acid salt, therebybeing insoluble is the water. Again, an aqueous layer (containing acidsalt of mycophenclate mofetil) layer and an organic layer was thusformed. The aqueous layer was extracted with ethyl acetate (100 ml foreach extraction) twice to remove the unreacted methyl mycophenolate.

[0019] The aqueous layer containing the hydrochloric acid salt ofmycophenolate mofetil was now added therein with 20% sodium hydroxideaqueous solution to be basic (pH=7.7) to neutralize the hydrochloricacid and recover the mycophenolate mofetil in the aqueous solution.

[0020] Ethyl acetate was provided to twice extract the mycophenolatemofetil from the aqueous solution, each extraction using 100 ml of ethylacetate. The extracts of ethyl acetate were combined as an organic layerand washed with 100 ml aqueous solution of saturated sodium bicarbonate.

[0021] The organic layer was purified as being dried by anhydrousmagnesium sulfate, filtered, and evaporated under reduced pressure toobtain 23.2 grams of mycophenolate mofetil, with high purity of 99.9%and high yield of 89.5%.

[0022] From the above-mentioned example, it is understood that thepresent invention may produce mycophenolate mofetil with high purity andhigh yield in a short reaction time period to thereby reduce theproduction cost and prevent from wasting of energy to be superior to theprior arts.

I claim:
 1. A process for making mycophenolate mofetil comprising: transesterification by reacting alkyl mycophenolate with 2-morpholinoethanol in the presence of catalyst to obtain the mycophenolate mofetil.
 2. A process for making mycophenolate mofetil comprising the steps of: A. conducting a transesterification by reacting an alkyl mycophenolate with 2-morpholinoethanol in the presence of an organic solvent and a catalyst selected from the group consisting of alkaline metal salt, alkaline earth metal salt, tin oxide and stannous oxide to produce crude mycophenolate mofetil; B. adding an acid aqueous solution into said crude mycophenolate mofetil to form an acid salt of mycophenolate mofetil to be soluble in the acid aqueous solution to be separated from the unreacted reactants insoluble in the acid aqueous solution; C. basifying the acid aqueous solution to be a base equeous solution by adding a base therein; and D. extracting the mycophenolate mefetil from the base aqueous solution by an extracting organic solvent, and purifying the mycophenolate mofetil.
 3. A process according to claim 2, wherein said alkyl mycophenolate is selected from the group consisting of: methyl mycophenolate, ethyl mycophenolate, propyl mycophenolate and butyl mycophenolate.
 4. A process according to claim 2, wherein said catalyst is dibutyltin oxide.
 5. A process according to claim 2, wherein said extracting organic solvent is selected from the group consisting of: benzene, toluene, xylene, ethyl acetate, dichloro methane, and the mixture thereof. 